5A8Y

Crystal Structure of human neutrophil elastase in complex with a dihydropyrimidone inhibitor

5A8Y の概要

• エントリーDOI: 10.2210/pdb5a8y/pdb
• 関連するPDBエントリー: 5A8X 5A8Z
• 分子名称: NEUTROPHIL ELASTASE, 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-[alpha-L-fucopyranose-(1-6)]2-acetamido-2-deoxy-beta-D-glucopyranose, alpha-L-fucopyranose-(1-6)-2-acetamido-2-deoxy-beta-D-glucopyranose, ... (7 entities in total)
• 機能のキーワード: trypsin family fold, protease, hydrolase, hydrolase-inhibitor complex
• 由来する生物種: HOMO SAPIENS (HUMAN)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 25033.57

構造登録者

vonNussbaum, F.,Li, V.M.,Meibom, D.,Anlauf, S.,Bechem, M.,Delbeck, M.,Gerisch, M.,Harrenga, A.,Karthaus, D.,Lang, D.,Lustig, K.,Mittendorf, J.,Schaefer, M.,Schaefer, S.,Schamberger, J. (登録日: 2015-07-17, 公開日: 2016-08-03, 最終更新日: 2024-11-06)

主引用文献

Von Nussbaum, F.,Li, V.M.,Meibom, D.,Anlauf, S.,Bechem, M.,Delbeck, M.,Gerisch, M.,Harrenga, A.,Karthaus, D.,Lang, D.,Lustig, K.,Mittendorf, J.,Schafer, M.,Schafer, S.,Schamberger, J.
Potent and Selective Human Neutrophil Elastase Inhibitors with Novel Equatorial Ring Topology: In Vivo Efficacy of the Polar Pyrimidopyridazine Bay-8040 in a Pulmonary Arterial Hypertension Rat Model.
Chemmedchem, 11:199-, 2016

PubMed Abstract: Human neutrophil elastase (HNE) is a key driver of inflammation in many cardiopulmonary and systemic inflammatory and autoimmune conditions. Overshooting high HNE activity is the consequence of a disrupted protease-antiprotease balance. Accordingly, there has been an intensive search for potent and selective HNE inhibitors with suitable pharmacokinetics that would allowing oral administration in patients. Based on the chemical probe BAY-678 and the clinical candidate BAY 85-8501 we explored further ring topologies along the equator of the parent pyrimidinone lead series. Novel ring systems were annulated in the east, yielding imidazolo-, triazolo-, and tetrazolopyrimidines in order to ensure additional inhibitor-HNE contacts beyond the S1 and the S2 pocket of HNE. The western annulation of pyridazines led to the polar pyrimidopyridazine BAY-8040, which combines excellent potency and selectivity with a promising pharmacokinetic profile. In vivo efficacy with regard to decreasing cardiac remodeling and amelioration of cardiac function was shown in a monocrotaline-induced rat model for pulmonary arterial hypertension. This demonstrated in vivo proof of concept in animals.

PubMed: 26333652
DOI: 10.1002/CMDC.201500269

実験手法

X-RAY DIFFRACTION (1.9 Å)